Aligning with the NIH-NIDDK End-Stage Renal Disease (ESRD) Program's goal of promoting research to reduce the morbidity and mortality from ESRD, this proposal focuses on understanding the fundamental causes of the excess morbidity and mortality seen in dialysis patients in an effort to develop new targeted therapies. Candidate: Sahir Kalim completed his medical degree at the University of Vermont, his internal medicine training at the Mount Sinai Hospital in New York City, and his nephrology fellowship training at the combined Massachusetts General Hospital (MGH)/ Brigham and Women's Hospital Nephrology Fellowship Program. He recently completed a Master's Degree in Medical Science at Harvard Medical School (HMS). Dr. Kalim holds a faculty appointment in the MGH Nephrology Division and at HMS. His long term goal is to become an R01 funded investigator with expertise in ESRD, uremic toxicity, and human trials. Environment and Mentors: MGH and HMS offer a highly reputed clinical research training environment with a large pool of exceptional research faculty and several resources of particular value to junior investigators. Dr. Kalim's mentors provide complementary expertise: Dr. Ravi Thadhani is Director of Clinical Research as well as Chief of the MGH Nephrology Division and Dr. Ananth Karumanchi is a Howard Hughes Investigator whose lab has made several basic science contributions directly relevant to this proposal. Both Drs. Thadhani and Karumanchi have a robust track record of mentorship and a strong commitment to Dr. Kalim's training. Research: Growing evidence suggests a harmful protein modification known as carbamylation occurs in the setting of elevated urea levels from kidney failure, yet significant gaps persist in our knowledge of this process. This proposal examines the epidemiology of protein carbamylation in ESRD and how novel interventions might reduce carbamylation and improve health. Aim 1 utilizes existing data and blood samples, obtained as part of a large prospective observational cohort study of dialysis patients, to identify which variables influence carbamylation, which clinical outcomes carbamylation associates with, and how different dialysis modalities effect carbamylation levels. Studying over 500 individuals to understand the epidemiology of protein carbamylation-its mediators and its consequences-will improve our knowledge of the unique pathophysiology of ESRD and inform approaches to treatment. Notably, carbamylation occurs on both proteins and free amino acids and these targets effectively compete with each other for binding. Preliminary data suggest giving amino acid supplementation to dialysis patients significantly reduces carbamylation. Thus, Aim 2 of this proposal is a randomized clinical trial in 60 maintenance hemodialysis patients testing the effects of amino acid supplementation on carbamylation and clinical outcomes. Together, understanding the effects of protein carbamylation in ESRD and how best to treat it could yield new metrics by which to assess dialysis efficacy as well as new therapeutic approaches to improve patient outcomes in ESRD.